Design, Synthesis, and Pharmacological Evaluation of <i>N</i>-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors

Kümmerle, Arthur Eugen; Schmitt, Martine; Cardozo, Suzana V.S.; Lugnier, Claire; Villa, Pascal; Lopes, Alexandra Basilio; Romeiro, Nelilma C.; Justiniano, Hélène; Martins, Marco A.; Fraga, Carlos A.M.; Bourguignon, Jean‐Jacques; Barreiro, Eliezer J.

doi:10.1021/jm300514y

Cited by 106 publications

(84 citation statements)

References 89 publications

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“…CAS registry number: 5785-06-8. Analytical and spectral data is consistent with those reported in the literature 24 . …”

Section: Preparation Of 3-methoxybenzoic Acid Hydrazide (1)supporting

confidence: 90%

“…The compound was prepared according to a procedure from the literature 24 . CAS registry number: 5785-06-8.…”

Section: Preparation Of 3-methoxybenzoic Acid Hydrazide (1)mentioning

confidence: 99%

“…First hydrazides of 3-methoxybenzoic acid (1) and 4-tert-butylbenzoic acid (2) were synthesized with the use of the methods described earlier 24,25 by the reaction of commercially available methyl esters of above mentioned carboxylic acids with hydrazine hydrate. Then the synhtesized hydrazides were subjected to the condensation reactions with corresponding substituted aromatic aldehydes what allowed us to obtain appropriate hydrazide-hydrazone derivatives …”

Section: Chemistrymentioning

confidence: 99%

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Hydrazide-hydrazones of 3-methoxybenzoic acid and 4-tert-butylbenzoic acid with promising antibacterial activity against Bacillus spp

Popiołek¹,

Biernasiuk

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 28 hydrazide-hydrazones of 3-methoxybenzoic and 4-tert-butylbenzoic acid were synthesized and screened in vitro against the panel of reference strains of bacteria and fungi with the use of the broth microdilution method according to EUCAST and CLSI guidelines. Five of the synthesized compounds were found to exhibit high bacteriostatic or bactericidal activity against Gram-positive bacteria. The antimicrobial activity of compounds 13, 14, and 16 against Bacillus spp. was higher than that of commonly used antibiotics, like cefuroxime or ampicillin.

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“…CAS registry number: 5785-06-8. Analytical and spectral data is consistent with those reported in the literature 24 . …”

Section: Preparation Of 3-methoxybenzoic Acid Hydrazide (1)supporting

confidence: 90%

“…The compound was prepared according to a procedure from the literature 24 . CAS registry number: 5785-06-8.…”

Section: Preparation Of 3-methoxybenzoic Acid Hydrazide (1)mentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Hydrazide-hydrazones of 3-methoxybenzoic acid and 4-tert-butylbenzoic acid with promising antibacterial activity against Bacillus spp

Popiołek¹,

Biernasiuk

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…N-Methylation of NAH 1, which results in N-methyl-NAH 3a, causes conformational restriction of the amide bond, thus preventing its rotation, as previously described by our group [17,26]. In fact, this modification abolished the duplication of the signals in the NMR spectra.…”

mentioning

confidence: 54%

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

et al. 2013

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Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1 H-and 13 C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1 H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the OPEN ACCESSMolecules 2013, 18 11684 electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the ΔG ≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond-related conformations.

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“…28 Briefly, the lavage fluid was centrifuged, and cell pellets were resuspended in 250 μL of PBS containing 10 mM EDTA for enumeration of total leukocytes by means of a Neubauer chamber. Cytospin slides were prepared from BAL fluid (BALF) and stained with MayGrunwald-Giemsa stain.…”

Section: Cell Recovery From the Airway Lumenmentioning

confidence: 99%

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

D'Almeida¹,

Oliveira²,

Souza³

et al. 2017

IJN

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Acute respiratory distress syndrome (ARDS) is a severe clinical condition of respiratory failure due to an intense inflammatory response with different etiologies. Despite all efforts, therapy remains limited, and ARDS is still associated with high mortality and morbidity. Plants can provide a vast source of active natural products for the discovery of new drugs. α-bisabolol (α-bis), a constituent of the essential oil from chamomile, has elicited pharmacological interest. However, the molecule has some limitations to its biological application. This study was conducted to develop a drug delivery system using lipid-core nanocapsules (LNCs) to improve the anti-inflammatory effects of orally administered α-bis. α-bis-loaded LNCs (α-bis-LNCs) were prepared by interfacial deposition of poly(ε-caprolactone) and orally administered in a mouse model of ARDS triggered by an intranasal administration of lipopolysaccharide (LPS). We found that α-bis-LNCs (30, 50, and 100 mg kg −1 ) significantly reduced airway hyperreactivity (AHR), neutrophil infiltration, myeloperoxidase activity, chemokine levels (KC and MIP-2), and tissue lung injury 18 hours after the LPS challenge. By contrast, free α-bis failed to modify AHR and neutrophil accumulation in the bronchoalveolar lavage effluent and lung parenchyma and inhibited elevation in the myeloperoxidase and MIP-2 levels only at the highest dose. Furthermore, only α-bis-LNCs reduced LPS-induced changes in mitogen-activated protein kinase signaling, as observed by a significant reduction in phosphorylation levels of ERK1/2, JNK, and p38 proteins. Taken together, our results clearly show that by using LNCs, α-bis was able to decrease LPS-induced inflammation. These findings may be explained by the robust increase of α-bis concentration in the lung tissue that was achieved by the LNCs. Altogether, these results indicate that α-bis-LNCs should further be investigated as a potential alternative for the treatment of ARDS.

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Design, Synthesis, and Pharmacological Evaluation of N-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors

Cited by 106 publications

References 89 publications

Hydrazide-hydrazones of 3-methoxybenzoic acid and 4-tert-butylbenzoic acid with promising antibacterial activity against Bacillus spp

Hydrazide-hydrazones of 3-methoxybenzoic acid and 4-tert-butylbenzoic acid with promising antibacterial activity against Bacillus spp

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

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Design, Synthesis, and Pharmacological Evaluation of N-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors

Cited by 106 publications

References 89 publications

Hydrazide-hydrazones of 3-methoxybenzoic acid and 4-tert-butylbenzoic acid with promising antibacterial activity against Bacillus spp

Hydrazide-hydrazones of 3-methoxybenzoic acid and 4-tert-butylbenzoic acid with promising antibacterial activity against Bacillus spp

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

&alpha;-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

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α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice